The present invention relates to a process for preparing intermediates of aromatic amidine derivatives which have anticoagulation action based on excellent activated coagulation factor X (hereinafter abbreviated as FXa) inhibitory action and are described in Japanese Patent Application Laid-Open (kokai) No. 5-208946.
As intermediates of the aromatic amidine derivatives described in Japanese Patent Application Laid-Open (kokai) No. 5-208946, compounds of the following formulas (V), (Va), and (Vb), a nd salts thereof have conventionally been known: 
[wherein R1 represents a protective group for a nitrogen atom and R3 represents a hydrogen atom, an aralkyl group, or an alkyl group having 1 to 6 carbon atoms]; 
[wherein R1 and R3 have the same meanings as described above]; and 
[wherein R1 and R3 have the same meanings as described above]. Processes for preparing the above compounds are also described in the cited publication.
A typical process for preparing these intermediates comprises the following steps:
brominating 7-methyl-2-naphthalenecarbonitrile to thereby form 7-Bromomethyl-2-naphthalenecarbonitrile (first step);
further converting the 7-Bromomethyl-2-naphthalenecarbonitrile to a phosphonium salt, [(7-cyano)-2-naphthyl)methyl]triphenylphosphonium bromide (second step);
synthesizing ethyl 2-[4-[[(3S)-1-(tert-Butoxycarbonyl)-3-hydroxypyrrolidinyl]oxylphenyl]-2-oxoacetate using a Mitsunobu reaction of ethyl 2-(4-hydroxyphenyl)-2-oxoacetate and (3R)-1-(tert-Butoxycarbonyl)-3-hydroxypyrrolidine (third step);
subjecting the obtained ethyl 2-[4-[[(3S)-1-(tert-Butoxycarbonyl)-3-hydroxypyrrolidinyl]oxy]phenyl]-2-oxoacetate and the [(7-cyano)-2-nahpthyl)methyl]-triphenylphosphonium bromide to a Wittig reaction (fourth step);
further performing catalytic hydrogenation to thereby form compounds represented by formula (V) or (Va) (fifth step); and
dissolving compounds represented by formula (Va) in ethanol with heat, adding a small amount of sodium hydride thereto, and causing crystallization while stirring the mixture at room temperature, to thereby obtain compounds represented by formula (Vb) (sixth step).
However, the above-described prior art process has the following drawbacks:
1) bromination in the first step is performed in tetrachloromethane, which is a suspected carcinogen;
2) the product of the first step, i.e., 7-Bromomethyl-2-naphthalenecarbonitrile, causes skin irritation when isolated as crystals;
3) comparatively expensive reagents, diethyl azodicarboxylate and 1,8-diazabicyclo[5.4.0]-7-undecene, are used;
4) by-products formed both in the third step and the fourth step behave as catalyst poisons in the catalytic hydrogenation of the fifth step, and in order to remove the by-products, it requires purification by silica gel column chromatography;
5) palladium oxide monohydrate-barium sulfate, which is a catalyst of the catalytic hydrogenation, must be prepared upon use; and
6) the yield of the sixth step is low and sodium hydride, which involves a safety problem, is used.
Briefly, the prior art process is unsatisfactory as an industrial process.
Accordingly, an object of the present invention is to provide an industrially satisfactory process for preparing compounds represented by formulas (V), (Va), and (Vb) and salts thereof, by use of safe, inexpensive, and easily available starting material(s) and auxiliary material(s) and without a silica gel chromatographic purification step, as well as to provide an industrial process for preparing intermediates of aromatic amidine derivatives which are described in Japanese Patent Application Laid-Open (kokai) No. 5-208946.
In view of the foregoing, the present inventors have conducted earnest studies and have found
that halogenation can be effectively performed in an alkylnitrile solvent in a first step, which permits the reaction to proceed to the next step without isolation of the product;
that use of a pyrrolidinyloxyphenylacetic acid derivative, obtained through condensation of 4-hydroxyphenylacetic acids and sulfonyloxypyrrolidines, as one starting material provides a compound represented by formula (V) or (Va) without requiring reaction to form a phosphonium salt and catalytic hydrogenation, and further without need for preparation of an expensive reagent or a reagent required upon use; and
that applying a base to a diasteromeric mixture of compounds represented by formula (Va) results in easy formation of compounds represented by formula (Vb). The present invention was accomplished based on these findings.
The present invention is generally represented by the following reaction schemes I and II: 
[(wherein R1 represents a protective group for a nitrogen atom; R2 represents a methanesulfonyl group or a p-toluenesulfonyl group; R3 represents a hydrogen atom, an aralkyl group, or an alkyl group having 1 to 6 carbon atoms; and X1 represents a leaving group].
Accordingly, the present invention provides a process for preparing a compound represented by formula (III) or (IIIa) or salts thereof through reaction of a compound represented by formula (I) or (Ia) and a compound represented by formula (II) in the presence of a base.
The present invention also provides a process for preparing a compound represented by formula (V) (or (Va)) or salts thereof through reaction of a compound represented by formula (III) (or (IIIa)) or a salt thereof and a compound represented by formula (IV) in the presence of a base.
The present invention further provides a process for preparing a compound represented by formula (Vb) through reaction of a compound represented by formula (Va) and a base.
The present invention still further provides a process for preparing a compound represented by formula (IVa): 
[wherein X2 represents a halogen atom]; through halogenation of a compound represented by formula (VII) in an alkylnitrile solvent.
Of the compounds appearing in the above-described reaction schemes, some are novel compounds that have been newly found in the present invention. Accordingly, the present invention is also directed to such novel compounds which are useful as synthesis intermediates.
The present invention further provides compounds represented by formula (III): 
[(wherein R1 and R2 have the same meanings as described above], and salts thereof.
The present invention further provides compounds represented by formula (IIIa): 
[wherein R1 and R3 have the same meanings as described above], and salts thereof.
The present invention still further provides compounds represented by formula (Vc): 
[wherein R1c represents a tertiary butoxycarbonyl group and R3c represents a hydrogen atom, an aralkyl group, or an alkyl group having 1 to 6 carbon atoms (other than an ethyl group)], and salts thereof.
The present invention yet further provides compounds represented by formula (Vd): 
[wherein R1d represents a benzyl group and R3d represents a hydrogen atom, an aralkyl group, or an alkyl group having 1 to 6 carbon atoms], and salts thereof.
The present will next be described in detail. Firstly, the substituents of the compounds according to the present invention are described.
R1 represents a protective group for the nitrogen atom. Protective groups which are typically used may be employed for the protective group. Examples include a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group, a benzyl group, a formyl group, an acetyl group, and a triphenylmethyl group. In the present invention, a tert-butoxycarbonyl group or a benzyl group is preferred.
R2 represents a methanesulfonyl group or a p-toluenesulfonyl group.
The alkyl group having 1 to 6 carbon atoms represented by R3 may be linear, branched, or cyclic, and examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, a hexyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. The aralkyl group is a group formed of an alkyl group having 1 to 6 carbon atoms and an aryl group, and examples thereof include a benzyl group and a naphthylmethyl group. The group R3 in the present invention is preferably an alkyl group having 1 to 6 carbon atoms, more preferably a methyl group or an ethyl group.
X1 represents a leaving group. As the leaving group, any such a group which is usually used may be employed, and examples include a halogen atom, a methanesulfonyloxy group, and a p-toluenesulfonyloxy group. As used herein, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Of these, a bromine atom is particularly preferred.
X2 represents a halogen atom. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Among others, a bromine atom is preferred.
The compounds represented by formula (I) or formula (Ia), the compounds represented by formula (II), and the compounds represented by formula (VII) used in the present invention are easily available known compounds or compounds which can easily be produced according to literature.
The compounds represented by formula (I) are known compounds, and optically active (3R)-1-(tert-Butoxylcarbonyl)-3-methanesulfonyloxypyrrolidine (see Japanese Patent Application Laid-Open (kokai) No. 2-28180) and optically active (3R)-1-(tert-Butoxylcarbonyl)-3-p-toluenesulfonyloxypyrrolidine (see WO 9200295) represented by formula (Ia) are also known compounds.
Among the compounds represented by formula (II), methyl p-hydroxyphenylacetate and ethyl p-hydroxyphenylacetate are known compounds. Other p-hydroxyphenylacetic acid alkyl esters can easily be produced from the condensation use of the corresponding alcohol and easily available p-hydroxyphenylacetic acid.
7-Halomethyl-2-naphthalenecarbonitrile, which is an example compound of formula (IV), is also a known compound (Japanese Patent Application Laid-Open (kokai) Nos. 5-208946 and 7-17937).
The production process of the present invention will next be described in detail.
[Step A] Method for Preparing a Compound Represented by Formula (III) or Formula (IIIa) or Salts thereof:
In order to obtain a compound represented by formula (III) or formula (IIIa) or salts thereof, a compound represented by formula (I) or formula (Ia) is reacted with a compound represented by formula (II) in the presence of a base and optionally an catalyst.
No particular limitation is imposed on the solvent used in this step so long as it provides no adverse effect on the reaction. Examples of the solvent include organic solvents such as aprotic polar solvents, ethers, aromatic hydrocarbons, and alcohols; mixtures of the organic solvents; and mixtures of the organic solvents and water.
Examples of the aprotic polar solvents include N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and acetonitrile. Examples of the ethers include tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, and triethylene glycol dimethyl ether. Examples of the aromatic hydrocarbons include benzene, toluene, and xylene. Examples of the alcohols include methanol and ethanol. Among the solvents, aprotic polar solvents or aromatic hydrocarbons are preferably used, with N,N-dimethylformamide or toluene being more preferred.
No particular limitation is imposed on the base so long as it provides no adverse effect on the reaction, and a weak or strong base may be used. Examples of a strong base include an alkali metal hydride such as sodium hydride or lithium hydride; an alkaline earth metal hydride such as calcium hydride; an alkali metal alkoxide such as sodium methoxide, lithium methoxide, sodium ethoxide, lithium ethoxide, sodium tert-butoxide, or potassium tert-butoxide; an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide; and an alkali metal carbonate such as sodium carbonate or potassium carbonate. Strong bases are preferred. Particularly, an alkali metal hydride is preferred, with sodium hydride being more preferred.
Examples of the catalyst which is used in the present invention include phase-transfer catalysts and molecular sieves. Examples of the phase-transfer catalysts include oleophilic quaternary ammonium salts such as tetra(n-butyl)ammonium bromide, tetra(n-butyl)ammonium chloride, tetraethylammonium bromide, tetra(n-butyl)ammonium hydrogensulfide, triethylbenzylammonium bromide, or triethylbenzylammonium chloride; and crown ethers such as 18-crown-6,15-crown-5. Phase-transfer catalysts are preferred. Particularly, oleophilic quaternary ammonium salts are preferred, with tetra(n-butyl)ammonium bromide being more preferred. Addition of the catalysts increases the yield of the compounds represented by formula (III) or formula (IIIa) or salts thereof.
No particular limitation is imposed on the reaction temperature so long as it is not greater than the boiling point of the solvent. The reaction is typically performed within the temperature range from 0xc2x0 C. to about the boiling point of the solvent used, preferably at 60xc2x0 C.-110xc2x0 C. The reaction time varies in accordance with the reaction temperature, and the reaction is performed typically for 15 minutes to one day, preferably for 4 hours or less.
[Step B] Method for Preparing a Compound Represented by Formula (IV):
The compound represented by formula (IV) may be obtained through a known method, and is preferably obtained through halogenation of a compound represented by formula (VII) in an alkylnitrile solvent. A radical initiator may be added during the halogenation.
No particular limitation is imposed on the alkylnitrile solvent so long as it provides no adverse effect on the reaction, and C2-C7 linear or branched alkylnitriles may be used. Examples of the C2-C7 linear or branched alkylnitriles include acetonitrile, propionitrile, n-butyronitrile, isobutyronitrile, valeronitrile, hexanenitrile, and heptanenitrile. Of these, linear or branched alkylnitriles having 2 to 4 carbon atoms such as acetonitrile, propionitrile, n-butyronitrile, or isobutyronitrile are preferred, with acetonitrile being more preferred.
No particular limitation is imposed on the radical initiator so long as it provides no adverse effect on the reaction, and examples thereof include peroxides such as dibenzoyl peroxide or azo compounds such as azobisisobutyronitrile. Instead of adding a radical initiator, operations such as light irradiation or heating may be performed. Of a variety of radical initoators, azo compounds are preferred, with 2,2xe2x80x2-azobisisobutyronitrile being particularly preferred.
The halogenation may be performed by adding a halogenating agent. No particular limitation is imposed on the halogenating agent so long as it provides no adverse effect on the reaction. Examples thereof include sulfuryl halides and N-halogenoimides. Of these, N-halogenoimides are preferred, with N-bromosuccinimide being more preferred.
No particular limitation is imposed on the reaction temperature so long as it is not higher than the boiling point of the solvent. The reaction is typically performed at 40xc2x0 C.-120xc2x0 C., preferably at about 80xc2x0 C. The reaction time depends on the reaction temperature, and the reaction is typically performed for one hour to one day, preferably for 1-4 hours.
[Step C] Method for Preparing a Compound Represented by Formula (V) or Formula (Va) or Salts thereof:
In order to obtain a compound represented by formula (V) or formula (Va) or a salt thereof, a compound represented by formula (III) or formula (IIIa) is reacted with a compound represented by formula (IV) in the presence of a base.
No particular limitation is imposed on the solvent in the step so long as it provides no adverse effect on the reaction. Examples of the solvent include organic solvents such as aprotic polar solvents, ethers, esters, aromatic hydrocarbons, and alcohols; mixtures of the organic solvents; and mixtures of the organic solvents and water.
Examples of the aprotic polar solvents include N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and acetonitrile. Examples of the ethers include tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, and triethylene glycol dimethyl ether. Examples of the esters include methyl acetate, ethyl acetate, methyl propionate, and ethyl propionate. Examples of the aromatic hydrocarbons include benzene, toluene, and xylene. Examples of the alcohols include methanol and ethanol. The mixtures of the organic solvents are preferably used. Of these, mixtures of an aprotic polar solvent and an aromatic hydrocarbon are preferred, with a mixture comprising N,N-dimethylformamide and toluene being more preferred.
No particular limitation is imposed on the base so long as it provides no adverse effect on the reaction, and a weak or strong base may be used. Examples of a strong base include an alkali metal hydride such as sodium hydride, or lithium hydride; an alkaline earth metal hydride such as calcium hydride; an alkali metal alkoxide such as sodium methoxide, lithium methoxide, sodium ethoxide, lithium ethoxide, sodium tert-butoxide, or potassium tert-butoxide; an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide; and an alkali metal carbonate such as sodium carbonate or potassium carbonate. Strong bases are preferred. Particularly, an alkali metal hydride is preferred, with sodium hydride being more preferred.
No particular limitation is imposed on the reaction temperature so long as it is not higher than the boiling point of the solvent, however, the reaction is preferably performed at comparatively low temperature in order to suppress a side reaction. The reaction is performed typically within the temperature range from xe2x88x9210xc2x0 C. to room temperature, preferably at 60xc2x0 C.-110xc2x0 C. The reaction time varies in accordance with the reaction temperature, and the reaction is performed typically for one hour to one day, preferably for 3-12 hours.
The thus-obtained 2-phenyl-3-naphthylpropionic acid derivatives, which are compounds represented by formula (V) or formula (Va), are important intermediates of aromatic amidine derivatives described in Japanese Patent Application Laid-Open (kokai) No. 5-208946.
Steps A and C; Steps B and C; or Steps A, B, and C may be performed continuously. Briefly, a compound represented by formula (III) or formula (IIIa) or a salt thereof that is obtained through Step A and a compound represented by formula (IV) or a salt thereof that is obtained through Step B may be used in the subsequent Step C without isolating the compounds at respective steps.
An example of the sequential steps will next be described. Firstly, in Step A, a compound represented by formula (III) or formula (IIIa) or a salt thereof is obtained through reaction in an aromatic hydrocarbon solvent by use of a phase-transfer catalyst in the presence of a strong base. Then, in Step B, a compound represented by formula (IV) obtained through reaction in an alkylnitrile is extracted with an aromatic hydrocarbon. Subsequently, a compound represented by formula (III) or formula (IIIa) or a salt thereof and a compound represented by formula (IV) are reacted, without isolating these compounds, in a solvent mixture comprising an aromatic hydrocarbon solvent containing an aprotic polar solvent in the presence of a strong base, to thereby obtain a compound represented by formula (V) or formula (Va) or a salt thereof.
The sequential steps requiring no operation such as isolation is preferred as an industrial process. In particular, since isolated crystals of 7-Bromomethyl-2-naphthalenecarbonitrile exhibit skin irritation, Step B and Step C are preferably performed sequentially.
(Step D] Method for Preparing an Optically Active Compound Represented by Formula (Vb):
In order to obtain a compound represented by formula (Vb) from a compound represented by formula (Va), a compound represented by formula (Va) may be reacted with a base.
Briefly, a compound represented by (Va) that is a mixture of an R-diastereomer and an S-diastereomer is reacted. with a base, to thereby obtain a compound represented by formula (Vb), which is an S-diastereomer.
Specifically, the R-diastereomer is dissolved in a solvent which is appropriate for inducing crystallization of the S-diastereomer and Is reacted in the dissolved state with a base, to thereby effect conversion from the R-diastereomer to the S-diastereomer. The target S-diastereomer Is then crystallized through the difference In solubility between the R-diastereomer and the S-diastereomer.
In this case, no particular limitation Is imposed on the solvent so long as it provides no adverse effect on the reaction, and there may be used a solvent which allows crystallization of compounds represented by formula (Vb). Specifically, protic solvents including water and alcohols may be used. These solvents may be used singly or in combination. The protic solvents may be blended with aprotic polar solvents, ethers, hydrocarbons, or mixtures thereof to thereby serve as a solvent.
Examples of the alcohols include methanol and ethanol. Examples of the aprotic polar solvents include N,N-dimethylformamide, dimethyl sulfoxide, and acetonitrile. Examples of the ethers include isopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, and triethylene glycol dimethyl ether. Examples of the hydrocarbons include benzene, toluene, xylene, n-hexane, and n-pentane.
No particular limitation is imposed on the base so long as it provides no adverse effect on the reaction. Examples of the strong base include alkali metal alkoxides such as sodium methoxide, lithium methoxide, sodium ethoxide, lithium ethoxide, sodium tert-butoxide, or potassium tert-butoxide; alkali metal amides such as sodium amides; and alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, and alkali metal carbonates such as sodium carbonate or potassium carbonate. Strong bases are preferably used. Of these, alkali metal alkoxides are preferred, with sodium ethoxide being more preferred.
The amount of the base is not limited so long as it provides no adverse effect on the reaction, and it is preferably 10-30% mol-equivalent based on the compound represented by formula (Va).
No particular limitation is imposed on the reaction temperature so long as it is not greater than the boiling point of the solvent. The reaction is performed typically in a temperature range from xe2x88x9210xc2x0 C. to room temperature, preferably in a range from 10xc2x0 C. to room temperature. The reaction time varies in accordance with the reaction temperature, and the reaction is performed typically for 30 minutes to several days, preferably for 20 hours or less.
The thus-obtained optically active 2-phenyl-3-naphthalenepropionic acid derivatives, which are compounds represented by formula (Vb), are important intermediates of aromatic amidine derivatives described in the cited reference.
The aromatic amidine derivatives or salts thereof may be prepared from compounds represented by formula (V), (Va), or (Vb) through a method described in Japanese Patent Application Laid-Open (kokai) No. 5-208946.